The goal of this renewal application is to improve the understanding of the pathophysiology of the bone fragility syndrome of osteoporosis and, thereby, rationalize and optimize its treatment. Specifically, it will test the interrelated hypotheses that the decline in bone mass and strength with age is a multi-factorial process and oxidative stress (OS) is a common underlying culprit of several different mechanisms, including aging per se; sex steroid deficiency; lipid oxidation; and endogenous hyperglucocorticoidism and failure of autophagy. Hormone therapies, such as estrogen replacement and intermittent RTH, owe their efficacy, at least in part, to antioxidant properties. To achieve the goal of the Program, three projects supported by three cores are proposed. Core A combines scientific management with biostatistics and administrative support; Core B provides design, production, characterization, and maintenance of genetically modified mice; and Core C provides histomorphometry, DEXA, micro-CT, and biomechanical measurements. Project 1 will determine the contribution of reactive oxygen species (ROS) amplification by p66shc or ROS attenuation by FoxOs in osteoblasts and osteoclasts to skeletal homeostasis and its deregulation with aging, the role of ROS in the effects estrogens on osteoblastic and osteoclastic cells, and the contribution of the loss of estrogen action in these cell types to skeletal involution. Specifically, it will test the hypotheses that increased ROS levels restrain te generation of committed osteoblast precursors by diverting ?-catenin from Wnt/Tcf to FoxO-mediated transcription, but increase osteoclast generation and survival; and that estrogens antagonize both of these effects by cell autonomous antioxidant actions mediated by ER. Project 2 will investigate the contribution of Alox15-mediated lipid oxidation to the adverse effects of aging, hyperlipidemia, and loss of estrogens on skeletal homeostasis, and the possibility that oxidized lipids intensify OS leading to reduced differentiation and survival of osteoblasts via FoxO- and PPAR?-mediated actions that decrease Wnt signaling. In addition it will test the hypothesis that intermittent PTH decreases OS by decreasing p66shc activation, suppressing Alox15 expression, and increasing the synthesis of antioxidant enzymes like Aldh3a1, leading to augmented Wnt signaling and increased bone formation. Finally, Project 3 will pursue seminal discoveries of this program that endogenous glucocorticoids contribute to the age-associated decrease in bone mass and strength by directly stimulating osteocyte apoptosis via increased OS and that this is opposed by the process of autophagy, which becomes less efficient with age. PUBLIC HEALTH RELEVANCE: This work should deepen our understanding of how aging predisposes to the development of osteoporosis and thereby increases the risk of fractures in the elderly. Such an understanding may prove useful for defining strategies to modulate regenerative responses and developing drugs targeting pathways that could simultaneously prevent (or even reverse) osteoporosis and other degenerative disorders caused by old age and oxidative stress. REVIEW OF INDIVUDUAL COMPONENTS CORE A: MANAGEMENT, ADMINISTRATION AND BIOSTATISTICS CORE; Dr. Stavros C. Manolagas, Core Leader (CL) DESCRIPTION (provided by applicant): As in the past, the goal of the Management, Administration and Biostatistics Core (A) is to assist the three Projects and the other two Cores by combining scientific management, administrative support, biostatistical expertise and common equipment maintenance into a single core function; and providing these services in a centralized and coordinated fashion. To achieve its goal, the Core will pursue the following specific aims: provide scientific leadership and management and monitor progress and compliance with the research objectives. This will be done by the PI and the Associate Program Directors, Drs. Jilka and O'Brien. The Core will also provide administrative support. This will be done by the PI and the Administrator of this Program Project, Mark Mosby. Mr. Mosby is also a Medical Service Manager for the Center for Osteoporosis and Metabolic Bones Diseases and the Division of Endocrinology and Metabolism. Mr. Mosby will be aided by the rest of the administrative staff of the Center for Osteoporosis and Metabolic Bone Diseases and the Division of Endocrinology and Metabolism. Furthermore, Core A will provide biostatistical expertise by Dr. Roberson, the Chair of the UAMS Department of Biostatistics, and Mr. Thostenson, a master's trained biostatistics research associate. Finally, this Core will be responsible for centralized common equipment maintenance. PUBLIC HEALTH RELEVANCE: Coordinating the work of a large program that examines how the elderly become susceptible to osteoporotic fractures should make it easier to understand the underlying disease and its causes. Moreover, it should facilitate the coordination of efforts that may lead to the discovery of treatments that could simultaneously prevent (or even reverse) osteoporosis and combat additional degenerative disorders caused by old age.